ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.916A>G (p.Ile306Val) (rs62642934)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000169485 SCV000852135 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: MAF = 2.0e-5; PP3: Software agrees on a damaging effect.; PS3: Mutation ID#1, 18% residual enzyme activity (PMID:18590700); PM3: I306V / F55L (pathogenic in ClinVar) in a single patient with mild HPA (PMID:18299955); PP4_Moderate: BH4 defect excluded in all patients--single patient with mild hyperphe (Bercovich, 2008). (PMID:18299955). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate).
Fulgent Genetics,Fulgent Genetics RCV000169485 SCV000611226 likely pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169485 SCV000696473 pathogenic Phenylketonuria 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The PAH c.916A>G (p.Ile306Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121200 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant was reported in numerous individuals in the literature, mainly associated with mild-PKU or hyperphenylalaninemia. In addition, in vitro assays show the variant to result in reduced PAH activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000169485 SCV000833414 pathogenic Phenylketonuria 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 306 of the PAH protein (p.Ile306Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs62642934, ExAC 0.002%). This variant has been observed in multiple individuals affected with PAH-related disease as homozygous or in combination with other PAH variants (PMID: 1358789, 18299955, 23430547, 23764561). ClinVar contains an entry for this variant (Variation ID: 618). Experimental studies have shown that this missense change impairs PAH enzyme activity in vitro (PMID: 25596310, 17924342, 11161839). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000089157 SCV001249174 pathogenic not provided 2019-06-01 criteria provided, single submitter clinical testing
OMIM RCV000000649 SCV000020799 pathogenic Hyperphenylalaninemia, non-pku 1992-09-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089157 SCV000119771 not provided not provided no assertion provided not provided
Counsyl RCV000169485 SCV000220937 pathogenic Phenylketonuria 2016-01-21 no assertion criteria provided clinical testing
Natera, Inc. RCV000169485 SCV001463131 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.